Skeletal metastases are frequent complications of many cancers, causing bone complications (fractures, bone pain, disability) that negatively affect the patient's quality of life. Here, we first discuss the burden of skeletal complications in cancer bone metastasis. We then describe the pathophysiology of bone metastasis. Bone metastasis is a multistage process: long before the development of clinically detectable metastases, circulating tumor cells settle and enter a dormant state in normal vascular and endosteal niches present in the bone marrow, which provide immediate attachment and shelter, and only become active years later as they proliferate and alter the functions of bone-resorbing (osteoclasts) and bone-forming (osteoblasts) cells, promoting skeletal destruction. The molecular mechanisms involved in mediating each of these steps are described, and we also explain how tumor cells interact with a myriad of interconnected cell populations in the bone marrow, including a rich vascular network, immune cells, adipocytes, and nerves. We discuss metabolic programs that tumor cells could engage with to specifically grow in bone. We also describe the progress and future directions of existing bone-targeted agents and report emerging therapies that have arisen from recent advances in our understanding of the pathophysiology of bone metastases. Finally, we discuss the value of bone turnover biomarkers in detection and monitoring of progression and therapeutic effects in patients with bone metastasis.

https://hal.archives-ouvertes.fr/hal-03102895/document

Bone metastasis: mechanisms, therapies, and biomarkers.

Bone metastasis is present in a high percentage of breast cancer (BCa) patients with distant disease, especially in those with the estrogen receptor-positive (ER+ ) subtype. Most cells that escape primary tumors are unable to establish metastatic lesions, which suggests that target organ microenvironments are hostile for tumor cells. This implies that BCa cells must achieve a process of speciation to adapt to the new conditions imposed in the new organ. Bone has unique characteristics that can be exploited by cancer cells: it undergoes constant remodeling and comprises diverse environments (including osteogenic, perivascular, and hematopoietic stem cell niches). This allows colonizing cells to take advantage of numerous adhesion molecules, matrix proteins, and soluble factors that facilitate homing, survival, and, eventually, metastatic outgrowth. However, in most cases, metastatic lesions enter into a latency state that can last months, years, or even decades, before forming a clinically detectable macrometastasis. This dormant state challenges the effectiveness of adjuvant chemotherapy. Detecting which tumors are more prone to metastasize to bone and developing new specific therapies that target bone metastasis represent urgent clinical needs. Here, we review the biological mechanisms of BCa bone metastasis and provide the latest options of treatments and predictive markers that are currently in clinical use or are being tested in clinical assays. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.5292

From latency to overt bone metastasis in breast cancer: potential for treatment and prevention.

The purpose of the present study was to characterize the prevalence, associated factors, and to construct a nomogram for predicting bone metastasis (BM) with different histological types of lung cancer. This study was a descriptive study that basing on the invasive lung cancer patients diagnosed between 2010 and 2014 in Surveillance, Epidemiology, and End Results program. A total of 125,652 adult patients were retrieved. Logistic regression analysis was conducted to investigate homogeneous and heterogeneous factors for BM occurrence. Nomogram was constructed to predict the risk for developing BM and the performance was evaluated by the receiver operating characteristics curve (ROC) and the calibration curve. The overall survival of the patients with BM was analyzed using the Kaplan–Meier method and the survival differences were tested by the log-rank test. A total of 25,645 (20.9%) were reported to have BM, and the prevalence in adenocarcinoma, squamous cell carcinoma, small cell lung cancer (SCLC), large cell lung cancer (LCLC), and non-small cell lung cancer/not otherwise specified lung cancer (NSCLC/NOS) were 24.4, 12.5, 24.7, 19.5 and 19.4%, respectively, with significant difference (P < 0.001). Male gender, more metastatic sites and lymphatic metastasis were positively associated with BM in all lung cancer subtypes. Larger tumor size was positively associated with BM in all the lung cancer subtypes except for NSCLC/NOS. Poorly differentiated histology was positively associated with adenocarcinoma, squamous cell carcinoma and NSCLC/NOS. The calibration curve and ROC curve exhibited good performance for predicting BM. The median survival of the bone metastatic lung cancer patients was 4.00 (95%CI: 3.89–4.11) months. With the increased number of the other metastatic sites (brain, lung and liver metastasis), the survival significantly decreased (p < 0.001). Different lung cancer histological subtypes exhibited distinct prevalence and homogeneity and heterogeneity associated factors for BM. The nomogram has good calibration and discrimination for predicting BM of lung cancer.

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Nomogram based on homogeneous and heterogeneous associated factors for predicting bone metastases in patients with different histological types of lung cancer.

The bone marrow has been long known to host a unique environment amenable to colonization by metastasizing tumor cells. Yet, the underlying molecular interactions which give rise to the high incidence of bone metastasis (BM) in breast cancer patients have long remained uncharacterized. In our study, in vitro and in vivo assays demonstrated that Brachyury (Bry) could promote breast cancer BM. Bry drives epithelial-mesenchymal transition (EMT) and promotes breast cancer aggressiveness. As an EMT driver, SOX5 involves in breast cancer metastasis and the specific function in BM. Chromatin immunoprecipitation (ChIP) assays revealed SOX5 is a direct downstream target gene of Bry. ChIP analysis and reporter assays identified two Bry-binding motifs; one consistent with the classic conserved binding sequence and the other a new motif sequence. This study demonstrates for the first time that Bry promotes breast cancer cells BM through activating SOX5. In clinical practice, targeting the Bry-Sox5-EMT pathway is evolving into a promising avenue for the prevention of bone metastatic relapse, therapeutic resistance and other aspects of breast cancer progression. Brachyury directly regulates the expression of SOX5 by binding to two motifs in its promoter region. The Bry-SOX5-EMT pathway may represent a potential target to develop treatments to prevent and treat bone metastasis from breast cancer.

Transactivation of SOX5 by Brachyury promotes breast cancer bone metastasis.

Introduction: On a global scale, the malignant growth of mammary gland is the most common type of cancer in women. In the progress of mammary carcinoma, osseous metastatic invasion has a pivotal significance because it is a frequent complication occurring at an early stage of the disease. Background: Bone metastases in breast cancer patients lead to increased mortality and decreased health-related quality of life. Therefore, early diagnostic assessment and treatment is requested. Meanwhile the progress of the disease should be monitored closely. Regarding health-related quality of life and lifetime prolongation, osseous metastases should be early diagnosed, therapied, and monitored. Up to date the gold standard is the whole-body scintigraphy. This kind of bone imaging features has high sensitivity but shows loss of specificity. Aim: This study aims to investigate the diagnostic versatility of bone markers in its resorption and formation function to detect bone metastases in patients with breast cancer. Patients, Materials, and Methods: For this purpose, the concentration of competing bone processing tumor markers in serums of 78 patients was detected and analyzed. Two groups of women with mammary carcinoma with and without osseous metastases were built to examine the presence (or absence) of statistically significant disparity of tumor marker concentration. The tumor markers employed in this study were the carboxyterminal collagen type I telopeptid (CTX), known as beta-crosslaps (β-CTx), the alkaline phosphatase (AP), and its isoenzymes (especially the bone-specific AP [B-AP]). Additionally, the tumor markers for breast cancer (CA 15-3 and CEA) were analyzed in both groups. Results: Our results provide evidence that in both groups, tumor markers such as β-CTx and B-AP were a promising tool for the detection and exclusion of bone metastases in breast cancer. This comprehensive investigation shows both β-CTx and B-AP are able to fulfill the conditions of a competent appliance to detect osseous metastases of patients with mammary carcinoma. Conclusion: Concerning the urgency of early and frequent detection, staging, and disease monitoring of mammary carcinoma with osseous metastases, this study renewed and underlined the importance of biochemical tumor markers – especially β-CTx and B-AP – and laid a clinical-based cornerstone to build up on a prospective research.

Expressiveness of Bone Markers in Breast Cancer with Bone Metastases.

Background: Adjuvant therapies can prevent/delay bone metastasis development in breast cancer We investigated whether serum bone turnover markers in early disease have clinical utility in identifying patients with a high risk of developing bone metastasis Methods: Markers of bone formation (N-terminal propeptide of type-1 collagen [P1NP]) and bone resorption (C-telopeptide of type-1 collagen [CTX], pyridinoline cross-linked carboxy-terminal telopeptide of type-1 collagen [1-CTP]) were measured in baseline (pretreatment blood samples from 872 patients from a large randomized trial of adjuvant zoledronic acid (AZURE-ISRCTN79831382) in early breast cancer Cox proportional hazards regression and cumulative incidence functions (adjusted for factors having a statistically significant effect on outcome) were used to investigate prognostic and predictive associations between recurrence events, bone marker levels, and clinical variables All statistical tests were two-sided Results: When considered as continuous variables (log transformed), P1NP, CTX, and 1-CTP were each prognostic for future bone recurrence at any time (P = 006, P = 009, P = 008, respectively) Harrell's c-indices were a P1NP of 057 (95% confidence interval [CI] = 051 to 063), CTX of 057 (95% CI = 051 to 062), and 1-CTP of 057 (95% CI = 052 to 063) In categorical analyses based on the normal range, high baseline P1NP (>70 ng/mL) and CTX (>0299 ng/mL), but not 1-CTP (>42 ng/mL), were also prognostic for future bone recurrence (P = 03, P = 03, P = 10, respectively) None of the markers were prognostic for overall distant recurrence; that is, they were bone metastasis specific, and none of the markers were predictive of treatment benefit from zoledronic acid Conclusions: Serum P1NP, CTX, and 1-CTP are clinically useful, easily measured markers that show good prognostic ability (though low-to-moderate discrimination) for bone-specific recurrence and are worthy of further study

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Hasina Thandar

Papers

Associations Between Serum Bone Biomarkers in Early Breast Cancer and Development of Bone Metastasis: Results From the AZURE (BIG01/04) Trial.